Treatment and prevention of the common cold using povidone-iodine

ABSTRACT

The present invention provides a method of treating and preventing the common cold and associated secondary illnesses in a human subject, when the common cold is caused by viruses. The method comprises applying to the nasal passages of the human subject at ambient temperature, an effective amount of a pharmaceutical preparation comprising povidone-iodine (PVP-I) at a concentration of greater than 0.10% w/v and less than 2.5% in which at least 50% of the PVP-I is not associated with liposomes or other particulate carriers.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/327,998, filed Jan. 20, 2017, currently pending, which is a 35 U.S.C.§ 371 National Phase conversion of PCT/AU2015/050378, filed Jul. 6,2015, which claims priority to Australian patent application no.2014206143, filed Jul. 23, 2014, the contents of each of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention is directed to methods for treatment and prevention ofthe common cold and its sequelae using topical preparations comprisingthe broad-spectrum antimicrobial agent povidone-iodine.

BACKGROUND OF THE INVENTION

Infective respiratory diseases are often broadly classified into upperrespiratory tract infections (URI) and lower respiratory tractinfections (LRI). The upper respiratory tract includes the oral cavity,nasal cavity, sinuses, middle ear, pharynx and larynx. The lowerrespiratory tract includes the trachea, bronchi, bronchioles and alveoliin the lungs. Each site can be the locus of a specific clinicalcondition that may have discrete presentation, causation and therapeuticchallenges. For this reason, it is not appropriate to talk about “upperrespiratory infections” or “lower respiratory tract infections” assingle, continuous or homogeneous conditions or therapeutic targets,because each term embraces a multiplicity of clinically discrete sites,causations, clinical conditions and treatment challenges. Further, itwould not be assumed in the art that any treatment disclosed as usefulfor a specific site or condition would necessarily indicate its utilityin another site or condition in the upper or lower respiratory tract.

The common cold is a widely-recognised URI, usually but not exclusivelydue to a viral infection of the nasal mucosa. Other common URI includetonsillitis, sinusitis and otitis media. Acute tonsillitis is aninfection of the palatine tonsils in the pharynx that is typicallycaused by bacteria belonging to the group A streptococcus genus, and iscommonly treated with penicillin. Sinusitis is an inflammatory conditionof the sinuses that can be due to infection, allergy or auto-immunecauses; where a bacterial cause is suspected, it is generally treatedwith an antibiotic. Otitis media is an infection of the middle ear oftencaused by bacteria and typically treated with antibiotics. Unlike thesethree cited conditions, currently, there is no effective treatment forthe common cold, which is generally caused by viruses.

While normally mild and self-limiting, the common cold, or simply the“cold” as it is generally known, has a very high incidence andprevalence and causes high morbidity, medical costs and productivitylosses, as well as contributing to an unduly high burden on the healthcare system. In the United States, adults experience an average of 2 to3 colds per year, while school children can have more than 10 a year, intotal contributing to an estimated 1 billion colds each year, resultingin up to 100 million doctor visits per year that cost the community anestimated $8 billion and add considerably to the burden on the medicalsystem, which in most advanced economies is already over-stretched. Inaddition, up to 200 million school days are missed annually and 150million workdays are lost due to employees having colds, and up toanother 150 million workdays lost due to parents staying home to carefor their sick children with colds. The total economic impact ofcold-related productivity losses has been estimated to potentiallyexceed $20 billion per year in the United States alone, with losses ofcomparable scale in other industrialized countries. Additionally,billions of dollars in the United States are spent each year onover-the-counter (OTC) medicines, supplements and other remedies thatmostly have little or no proven benefit, other some modest symptomaticrelief.

In addition, there is the indirect cost of antibiotic resistance causedin part by over-prescribing of antibiotics for colds by primary carephysicians, despite the fact that most colds are viral in origin andantibiotics only target bacteria. This is becoming an extremely seriousmedical problem because of the rise of drug-resistant pathogenicbacteria.

A further problem is that colds may predispose or precipitate otherconditions, notably otitis media, sinusitis and bronchitis, resulting inadditional morbidity, medical cost, productivity losses and antibioticuse.

In addition, for certain “at-risk” individuals, colds can lead toserious lower respiratory infections such as pneumonia, due to enhancedsusceptibility of the individuals or as a result of exacerbation of anunderlying respiratory disease. These at-risk individuals include peopleundergoing cancer chemotherapy or who are otherwise immune-compromised,and people with underlying respiratory disease including asthma, ChronicObstructive Pulmonary Disease (COPD), cystic fibrosis and emphysema. Insuch at-risk individuals, a cold can represent a serious threat thatcould lead to hospitalisation and potentially be life-threatening.

Despite all these important medical, economic and societal needs for aneffective treatment or preventative for the common cold and despitedecades of medical research in the field, there is no effectivetreatment available for colds and no vaccine exists to prevent colds.The reasons for this and the ongoing challenges are discussed below.

The common cold is a symptom complex initiated by an infection of thenasal mucosal cells inside the nasal cavity. For the purposes of thepresent invention, the term “nasal passages” will be used to include allthose sites within the nasal cavity and oropharynx that are the typicalsite of the infection that causes the common cold symptom complex. Whilea cold can cause or predispose other URI or LRI notably sinusitis,otitis media and bronchitis, these are regarded in the art and definedherein as secondary complications or sequelae of a cold and not part ofthe common cold condition itself.

Overwhelmingly, viruses are the cause of the infection of the nasalpassages leading to the condition known as the common cold. Indeed,identified and characterised viruses are known to cause at least 70% ofall colds, while a further approximately 25% of colds are non-specificwith respect to cause, but are believed to be viral, although in suchcases the specific viral cause has not been identified or characterised.Of the viruses known to cause colds, the most common is the humanrhinovirus (HRV), which is believed to account for at least half of allcolds and therefore the majority of viral colds. However, there are morethan 100 serotypes of HRV. In addition, there are many other virusesthat can cause colds including coronaviruses, influenza viruses,parainfluenza viruses and respiratory syncytial virus (RSV). In manycases, there are numerous strains or serotypes of each. Overall, anestimated 200 species, strains or serotypes of viruses can cause theinfection of the nasal passages that leads to the common cold.

Despite the range of potential infective causes, the symptoms of theclinical condition that results from the infection are generallysimilar. Symptoms may include sneezing, rhinorrhoea (runny nose), nasalcongestion, sore throat, coughing, headache, malaise, chills and myalgia(body aches and pains). It is the constellation of these symptoms or the“symptom complex” that defines the condition generally known as thecommon cold rather than the infection per se. Indeed, some infectedindividuals will present with no symptoms, i.e. have no cold, even whenthey can be shown microbiologically to have an infection of the nasalpassages. One reason for the idiosyncrasy is that the symptom complex isthe result of the body's reaction to the infection rather than theinfection itself.

The common cold starts as an infection of the cells lining the nasalpassages. Because most of the research in the field has focused on HRV,the clinical pathology of HRV colds has been much better characterizedthan other viral colds, although it is generally assumed that thepathology would be similar for most viral colds. For HRV colds, once acell is infected, the viruses multiply rapidly inside the cells andafter 8-10 hours cause the cell to burst and release large numbers ofinfectious progeny viruses into the nasal passages that can infect othercells to propagate the infection.

The cell damage caused by the infection triggers local cellular defencemechanisms, including the release of the chemical bradykinin that isbelieved to directly cause sneezing, rhinorrhoea, congestion, sorethroat and cough. These are known as the “local symptoms” of the commoncold.

In addition to these non-specific cellular defences, certain immunecells present in the nasal passages, particularly monocytes andgranulocytes, become engaged. Monocytes detect the presence of viralantigens or nucleic acid, typically RNA, and release cytokines, whichare pro-inflammatory chemicals that recruit other immune cells, notablygranulocytes, to the site of the infection or foreign material.Granulocytes, especially neutrophils in the case of colds, ingest anddestroy foreign material including invading microorganisms. They alsosecrete more cytokines to attract even more neutrophils to the site toaccelerate virus removal. However, as a side effect, the cytokines causea low grade fever, drowsiness, malaise, myalgia and headache. These areknown as the “systemic symptoms” of a cold, but are not unique to coldsand can occur to some extent whenever the immune system reacts toforeign proteins or nucleic acid, for example following a vaccination oras a result of a bacterial or viral infection anywhere in the body.

The constellation of these local and systemic symptoms represents a“symptom complex” that is characteristic of and defines the clinicalcondition known as a cold. The composition, severity and timing of thecommon cold symptom complex may vary from one individual to another,depending on their underlying health status and pre-existing conditions,such as immunodeficiency or asthma. It may also vary from one infectingvirus to another. The diverse range of viral causes and the range ofimpacts, from the comparatively mild through to serious and in someinstances fatal consequences of such infections, have presented majorchallenges for antiviral drug development in the field.

Once a subject is infected, cold symptoms start to appear 24-36 hoursafter the initial infection in the nasal passages and typically last 8-9days from the time of onset. During the first 4-5 days of the cold,large numbers of the infectious virus are produced and can be detectedin the nasal mucous, which is thought to be the principal vehicle fortransmission of the disease. Transmission occurs either throughaerosolisation during coughing and sneezing or by nose-blowing withother people then breathing in the virus-laden aerosol particles ortouching contaminated hands or surfaces. The substantial amount of nasalmucous produced during the first few days of the cold amplifies viralshedding from infected individuals and thereby the efficiency of thetransmission process. Further, research has shown that even after allsymptoms have disappeared, viral shedding from a cold may continue at alow level for a further 2-3 weeks.

Unlike many viral diseases, there is no vaccine for the common cold.Viral vaccines rely on the long-term immune memory of a particularvirus, so that when that virus re-presents, antibodies already exist toimmediately target the virus for destruction by various immune processesbefore it can cause an infection. However, the immunity derived from aninfection by one cold virus may be relatively short lived and restrictedto only one particular virus or serotype, whereas colds can be caused byup to 200 different viruses that are constantly evolving and therebyevading the antibody-mediated immune system. Thus, antibody-mediatedimmunity plays little practical or effective role in preventing thecommon cold in the population.

The alternative to prevention with a vaccine is treatment subsequent tothe infection, but there are several substantial challenges to treatinga cold. One of these is that there are many microorganisms that cancause a cold. In contrast, other infectious diseases typically have asingle microbial cause and an uncomplicated cause-symptom pathway.Examples are human immunodeficiency virus (HIV) that causes AIDS andherpes simplex virus (HSV) that causes cold sores. In each case,specific antiviral treatments are available that suppress or destroy thevirus responsible and thereby treat the symptoms of the disease. Thecommon cold is different to these diseases, because it can be the resultof an infection by any one of at least 200 different microorganisms.

Numerous attempts over many years have been made to develop antiviralagents as possible treatments for the common cold, but none hassucceeded in reaching the market. Human rhinovirus (HRV) is the primarycausative agent of the common cold and has been the focus of almost allantiviral drug development in the field. It is now known that there arethree HRV species, A, B and C, which fall within the genus Enterovirus(EV) and the family Picornaviridae. HRV species are further divided intoover a hundred distinct serotypes. Virtually all modern drug discoveryand development aimed at the common cold took place between the 1980sand the early 2000s and with few exceptions was aimed at developingdrugs that targeted HRV specifically. At one time or other during thisperiod, most of the major pharmaceutical companies attempted to developantiviral drugs targeting HRV, but by 2000 most programs had beenmothballed or abandoned. One exception was the drug pleconaril, whichwas still under development at the US company, Viropharma, during theearly 2000s. Pleconaril belongs to the capsid binder class of antiviralagents and binds to the coat or capsid of the virus to interfere withuncoating, which is an early, essential stage in the infectious cycle.Other capsid binders have been reported to interfere with the binding ofHRV to the ICAM-1 receptor on cells, also preventing entry of the virusinto cells. Viropharma's 2002 New Drug Application (NDA) received aunanimous vote against approval by the FDA Advisory Committee becausePhase III data indicated only a one-day reduction in cold duration whilepresenting a risk of cytochrome P450 induction leading to possibleundesirable side effects. Viropharma abandoned pleconaril and no otherantiviral drug for HRV has since progressed to a Phase III trial.

Apart from side effects, another limitation of HRV-specific antiviralagents is that they only target around half of all colds, at best. Thisnarrow spectrum problem for antiviral drugs is a particular concernbecause it may not be possible for physicians to distinguish thecausative organism based on the symptom complex presentation alone.Another limitation is that because they target specific receptor orprotein binding mechanisms, viruses can mutate and become resistant tothe agent, rendering the agent ineffective.

In addition to these HRV-specific approaches, a small number ofnon-specific approaches have been tested clinically, includinginterferon (a chemical produced naturally by cells to defend againstvirus infection), acidic buffers (because some viruses, especially HRV,are acid labile), and carrageenan (a seaweed extract). Interferon wasshown to be ineffective and acidic buffers reduced viral shedding buthad little impact on symptoms. Only carrageenan has been developedcommercially and introduced in a small number of countries, but it isnot approved in other countries including the US. The putative mechanismby which it works is to coat viruses and nasal surfaces with apolysaccharide that prevents attachment of the virus. Clinical studieswith carrageenan have shown mixed results, but it appears that if usedcontinuously during the symptomatic period of a cold it may slightlyreduce the duration of a cold, but may have little effect on theseverity of the symptoms.

Another challenge for any treatment for the common cold is that theintervention window is very narrow. Once symptoms are observed, theinfection may have been in progress for 24-36 hours and thereafter, byday 3 or 4 after first symptoms, the viral load in the nasal mucous isalready reduced to relatively low levels. This means that anytherapeutic intervention targeting the virus would have a limited windowof time in which to exert its effect and achieve significant symptomaticbenefits or effect in terms of reduction of cold duration. This presentsa practical problem for any drug that is available on prescription,because of the additional delay in obtaining access to the drug oncesymptoms are observed.

Further as already noted, the symptom complex is a product of the body'sreaction to the infection, rather than the infection per se. Once primedby the infection, the cellular defence mechanisms and immune responsecan remain engaged and are known to cause ongoing symptoms for severaldays even after the amount of virus in the nasal passages starts todecline. This limits the capacity of an antiviral agent to treat coldsymptoms based on its antiviral action alone.

In summary, there are formidable technical challenges to discovering anddeveloping an effective treatment and as a result, and despite decadesof research into possible treatments, no effective treatment has emergeddespite a very substantial medical, economic and social need to find,develop and commercialise an effective treatment for the common cold.

An effective treatment for the cold is generally considered in the artto be one that demonstrates a significant reduction in (1) the severityof symptoms, and/or (2) the duration of a cold. For the purposes ofevaluating symptom severity effects, those in the art commonly employ ameasure referred to as the total symptom score (TSS), which is a measureof the severity of the overall symptom complex based on an un-weightedcomposite of selected symptoms, typically calculated as a daily meanscore. The TSS is commonly comprised of five local and three systemicsymptoms, each assessed on an ordinal severity scale. The duration of acold is another important measure for clinical evaluations. One measureconsidered to be valid in the art is the time to alleviation of illness(TAI) which is determined as the time from initiation of treatment tothe time when rhinorrhoea is absent and no other individual symptom israted above ‘mild’ in severity.

In addition to these symptom-related measures, in studies where subjectsare deliberately infected with a cold virus, typically HRV, it ispossible to measure the viral load present at various times afterinfection as another important measure of the effectiveness of anyintervention in the common cold. This is commonly done by sampling themucous in the nasal passages, using swabs or nasal washings, anddetecting the amount or concentration of virus present using techniquessuch as cell culture or quantitative polymerase chain reaction (qPCR).

Other potentially important clinical endpoints in the evaluation of anycold therapy include the extent to which it (1) reduces the incidence orseverity of secondary illnesses such as otitis media, sinusitis andbronchitis, (2) reduces the incidence or severity of serious LRI anddisease exacerbations in at-risk individuals, and (3) prevents a coldoccurring when a subject is exposed to others with colds.

Topical treatment of colds by applying broad-spectrum chemicaldisinfectant-type agents to the nasal passages has not been attempted inthe field of respiratory diseases management. Such an approach may seemto have potential superficially, because of the ability of thedisinfectant to eradicate the virus directly from the nasal passages.However, in most cases there are serious limitations with such agentsincluding local burning, irritation, cellular toxicity, systemictoxicity and unpleasant odour. One chemical disinfectant that hasreduced toxic potential and recently has been shown to be safe to use inthe nose is povidone-iodine, commonly referred to as PVP-I.

Povidone-iodine (PVP-I) is a broad-spectrum topical microbicide that isknown to rapidly inactivate viruses, principally through the potentoxidative effects of free iodine on microbial proteins and nucleicacids. It is known in the art that the instantaneous potency of anyPVP-I solution is related to the concentration of free iodine releasedfrom the polymer carrier, where free iodine is typically less than 30ppm in PVP-I solutions, ensuring adequate potency for antimicrobialaction while avoiding the iodine-related stinging, burning and othertoxicities of traditional iodine solutions such as Lugol's solution,which is a solution of free iodine in potassium iodide. With a PVP-Isolution, the majority of the iodine remains within or bound to thecomplex and is only released as the exogenous free iodine is depleted,for instance as a result of its oxidative interaction with microbialprotein. In this way a relatively stable low level of free iodine ismaintained while a reservoir of inactive complex-bound iodine remainsclose to the site of action and ready for use as needed.

Because the oxidative effect of free iodine is potent and not protein ortarget specific, PVP-I has shown no susceptibility to viral resistancedevelopment despite more than 30 years of extensive usage as a topicalantiseptic. In addition, it has found some therapeutic utility as atopical agent to treat certain infective skin conditions, including acneand cold sores, which are caused by certain bacteria and herpes simplexvirus respectively. In some markets, including Australia and Japan, itis widely used as a throat gargle to treat sore throats, many of whichmay be associated with the common cold. However, as shown in onerandomised, controlled study by Satomura et al (“Prevention of upperrespiratory tract infections by gargling: a randomized trial.” AmericanJournal of Preventive Medicine 29.4 (2005): 302-307) while such garglingpractices may have a slight effect on the sore throat or pharyngealsymptoms of colds, they have no significant effect on nasal coldsymptoms or bronchial complications, and no benefit in terms of reducingthe incidence of the common cold.

The intranasal use of PVP-I has been extremely limited. PVP-I has beenproposed as an intranasal solution or cream for eradication ofantibiotic resistant bacteria, which can be inadvertently carried in thenasal passages and contribute to outbreaks of infection in the hospitalsetting. Hill and Casewell (“The in-vitro activity of povidone-iodinecream against Staphylococcus aureus and its bioavailability in nasalsecretions.” Journal of Hospital Infection 45.3 (2000): 198-205) testeda 5% PVP-I cream and concluded it may have a role in the prevention ofcolonization and infection caused by MRSA. Hollander et al(“Asymptomatic carriage of Klebsiella pneumoniae producingextended-spectrum b-lactamase by patients in a neurological earlyrehabilitation unit: Management of an outbreak.” Journal of HospitalInfection 48.3 (2001): 207-213) used a 1.25% PVP-I solution as a nasalspray to eradicate drug-resistant Klebsiella pneumonia from the nasalpassages of patients in a neurological rehabilitation unit. Kramer et al(“New aspects of the tolerance of the antiseptic povidone-iodine indifferent ex vivo models.” Dermatology 204.Suppl. 1 (2002): 86-91)confirmed that PVP-I solutions were also effective against MRSA andshowed that a PVP-I concentration of 1.25% or lower was suitable for usein the nose. In none of these cases was it suggested that PVP-Isolutions might have utility in treating or preventing the common coldas caused by a virus.

Despite its broad-spectrum, lack of resistance potential, utility incertain therapeutic applications and potential safety and utility in thenasal passages for eradication of drug-resistant bacteria, PVP-I hassignificant known limitations that would lead one skilled in the art toconclude that PVP-I would not be suitable, safe or effective as an agentto treat the common cold as caused by a virus.

One perceived limitation is that PVP-I is a topical agent that does notenter nasal cells, while the replication of cold viruses occursexclusively inside nasal cells. Those skilled in the art would concludethat any topical intervention such as PVP-I might temporarily degradethe viral load in the nasal mucous but would have no direct impact onthe ongoing infection inside the cells, and the latter would continue todrive bradykinin and cytokine production and thereby the symptomcomplex. In any case, as infected cells burst and released more virus,the viral load in the nasal mucous would be replenished, counteractingany depletive effects of PVP-I. This contrasts with the known usefulapplication of PVP-I to the nasal passages for eradication of bacteriasuch as MRSA, where the bacteria reside and replicate on the surface ofthe nasal cells and are not engaged in any active infection.

The process of mucociliary clearance also needs to be considered in theintranasal use of a topical agent, including PVP-I. Mucociliaryclearance is a natural cleaning process in the nasal passages wherebythe sweeping effect of the hairlike follicles on nasal cells, calledcilia, direct mucous towards the throat allowing the mucous to exit thenasal passages and ultimately be swallowed. This process is designed toconstantly clean the nasal passages by removal of contaminants includingmicroorganisms in nasal mucous. Gluck et al (“A clinical study on thetolerability of a liposomal povidone-iodine nasal spray: implicationsfor further development.” ORL 69.2 (2006): 92-99) showed that themucociliary clearance time was approximately 15 minutes in healthy nosesand that the application of a PVP-I preparation did not significantlyalter the clearance time. This would indicate that the maximum timeavailable for a topical intranasal preparation to have any antiviral orother local effect is approximately 15 minutes.

In addition, during a cold, any topical agent is further rapidly clearedby rhinorrhoea or runny nose, which according to Winther (“Rhinovirusinfections in the upper airway.” Proceedings of the American ThoracicSociety 8.1 (2011): 79-89) is the most common early symptom of thecommon cold in adults. Rhinorrhoea is due to watery fluid secretionsfrom nasal glands and goblet cells in the nasal passages that areprincipally designed to expel pathogens and other noxious materials fromthe nose. The volume of the fluids produced over the first several daysof a cold is substantial and according to Turner et al (“Efficacy oftremacamra, a soluble intercellular adhesion molecule 1, forexperimental rhinovirus infection: a randomized clinical trial.” JAMA281.19 (1999): 1797-1804) the amount of expelled fluids from theanterior nares is approximately 33 g over 7 days for an adult cold. Inaddition to these fluids secreted from the nostrils, a significantvolume of secreted fluids may be swallowed. Overall, during a cold, thehigh volume of secreted fluids would lead to dilution of any topicalagent and its accelerated clearance, causing a significant reduction inthe effective exposure time and effect in the nasal passages.Accordingly, one could reasonably conclude that the effective exposuretime for any topical agent such as PVP-I during a cold might be no morethan one or two minutes.

Another perceived limitation is that free iodine, the only activeantimicrobial moiety in PVP-I solutions, is rapidly consumed by nasalmucous because of the presence of mucins, glycoproteins present in nasalmucous secretions that contain a high concentration of cysteine, whichreacts readily with free iodine thereby inactivating it and making itunavailable for microbicidal action. Hill and Casewell (2000),previously referenced herein, demonstrated that nasal secretions reducedthe microbicidal activity of 5% PVP-I cream and calculated that 1.0 mLof nasal secretions inactivated the equivalent of 22.5 mg of PVP-I.Given the volume of a solution that can be applied into the nasalpassages and the likely concentration of PVP-I in such a solution, onewould conclude that most if not all of the free iodine available forrelease from a PVP-I intranasal application could be inactivated by thenasal secretions. This problem is amplified during the common cold whenthe volume of secretions and the level of mucins are greatly elevateddue to rhinorrhoea as discussed above. This is much less of a problemwhen PVP-I might be applied to the nasal passages for eradication ofMRSA or other resident bacteria, where mucous is limited and rhinorrhoeais not typical.

Another long-standing perceived limitation is that PVP-I has significanttoxicity for human cells. Kramer et al (2002), previously referencedherein, showed that a PVP-I concentration of 2.5% or greater was toxicto the nasal cilia and therefore generally unsuitable for use in thenose. A concentration of 1.25% or lower did not cause ciliotoxicity.However, even at or below 1.25%, PVP-I has significant toxicity forhuman immune cells particularly relevant to the treatment of the commoncold. Van den Broek et al (“Interaction of povidone-iodine compounds,phagocytic cells, and microorganisms.” Antimicrobial Agents andChemotherapy 22.4 (1982): 593-597) showed that PVP-I significantlyreduced the viability of granulocytes at concentrations above 0.05%,with virtually all granulocytes destroyed above 0.1%. Becausegranulocytes play a central role in the cellular immune processes thateliminate viruses during a cold, such toxicity generally would beconsidered undesirable for a cold treatment agent. Monocytes, which havean important immune signalling role in a cold and act in concert withgranulocytes to eliminate viruses, showed slightly more resilience toPVP-I, but were substantially degraded by PVP-I concentrations above0.1%. Because the toxicity of PVP-I to immune cells has been known inthe art since 1982, it has presented a long-standing perceived barrierto the development of PVP-I for many therapeutic applications. Again andin contrast, this is much less of a problem when PVP-I is applied to thenasal passages for eradication of resident bacteria, where immune cellsare not actively engaged in fighting an infection.

In an effort to combat the cellular toxicity problem of aqueous PVP-Ipreparations and expand the utility of PVP-I, researchers recently havesought to develop liposomal formulations of PVP-I wherein the majorityof the PVP-I is encapsulated in liposomes. Such liposomal PVP-Ipreparations have significantly reduced toxicity to human cells,potentially making them more suitable for certain intranasalapplications, but not the common cold. While trapping the majority ofthe PVP-I within liposomes reduces toxicity, it also slows the rateand/or extent of free iodine release, which also reduces its potencysuch that, and as further described herein, renders it unsuitable for anapplication such as the common cold and such liposomal PVP-Iformulations have never been proposed for the treatment or prevention ofthe common cold.

A further perceived limitation on the intranasal use of PVP-I is thatiodine absorption could lead to systemic toxicity due to its well-knowneffects on thyroid function. It is well known in the art that the nasalpassages represent a highly efficient portal for drugs and other agentsto enter the systemic circulation. Therefore, when using anyiodine-based product in the nasal passages, one needs to be extremelywary of the potential for excessive iodine absorption. In the UnitedStates, the National Institutes of Health guidelines state that the safeupper limit for total iodine ingestion by adults is 1,100 micrograms ofiodine per day. This easily could be exceeded by intranasal applicationsof a PVP-I preparation in the nose depending on the volume,concentration and frequency of application of the preparation.

A final and crucial perceived limitation of PVP-I is that it is haslimited activity against HRV, the virus responsible for the majority ofcolds. It is well known in the art that enveloped viruses are highlysusceptible to inactivation by various agents including PVP-I, whereasnon-enveloped or ‘naked’ viruses and particularly HRV, are resistant toinactivation by most chemical agents. A study by Reimer et al(“Antimicrobial effectiveness of povidone-iodine and consequences fornew application areas.” Dermatology 204.Suppl. 1 (2002): 114-120) showedthat against the enveloped virus, human influenza virus, PVP-I at verylow concentrations achieved a 4 log₁₀ reduction in viable virus count,which is generally considered a microbicidal effect, within a 30 secondexposure. This contrasts with human rhinovirus, a naked virus, wherePVP-I at any concentration barely achieved a 1 log reduction after 30seconds exposure and required 30 minutes exposure for a 4 log reduction.This further compares with another naked virus, adenovirus, where a 4log reduction required only 5 minutes exposure, reinforcing the factthat rhinovirus is one of the most resilient naked viruses and furtherthat activity of any agent against adenovirus or other naked viruses maynot be representative of the agent's activity against HRV. Further, andin any case, adenovirus is not a common or recognised cause of thecommon cold and therefore not relevant for comparison in the context ofthe common cold.

The relatively weak activity of PVP-I against HRV has been corroboratedby other studies. For example, Wutzler et al (“Virucidal activity andcytotoxicity of the liposomal formulation of povidone-iodine.” Antiviralresearch 54.2 (2002): 89-97) showed that PVP-I produced a 1.1 logreduction in HRV after 30 seconds exposure and required 30 minutes for amicrobicidal effect (4 log reduction), compared with a microbicidaleffect after only 5 minutes for adenovirus and after only 30 seconds forthe enveloped herpes simplex virus (HSV). Like adenovirus, HSV is not acommon or recognised cause of colds.

Kawana et al (“Inactivation of human viruses by povidone-iodine incomparison with other antiseptics.” Dermatology 195.Suppl. 2 (1997):29-35) tested the activity of PVP-I against multiple viruses andconfirmed the rapid microbicidal effect against enveloped viruses.However, PVP-I failed to produce a microbicidal effect against HRVwithin the maximum exposure period tested, which was 10 minutes. Giventhat these various studies were conducted under ideal in vitroconditions, one skilled in the art would assume that the performance ofPVP-I against HRV in vivo, especially in the face of inactivation andclearance processes, would be clinically negligible. For all the abovereasons, it would not be obvious that the intranasal application ofPVP-I would be effective as a treatment for the common cold. Further,PVP-I has never been developed or commercialised as an intranasaltreatment for the common cold and based on published information, hasnever been even assessed in a clinical study to determine itseffectiveness as a prospective treatment for the common cold. If it wereassessed in a controlled clinical study, those skilled in the art wouldassume that it would not meet the criteria for an effective treatment,namely that it would not cause a significant reduction in the severityof symptoms or the duration of a cold.

Despite all these limitations, the present inventors have surprisinglyfound that when used as an intranasal preparation according to themethods of the present invention, PVP-I is effective in reducing boththe severity of symptoms of a cold and the duration of a cold. Further,it has additional benefits with respect to reducing the viral load andviral shedding in the nasal passages during a cold, reducing secondaryillnesses, and reducing the risk or severity of serious LRI andexacerbations in at-risk individuals. Finally, methods are disclosedthat have utility in prevention of colds.

SUMMARY OF THE INVENTION

The present invention involves methods for the treatment and preventionof the common cold, including certain sequelae and secondary illnesses,where the causative or potentially causative agent of the common cold isa virus. In all cases, the methods involve the application at ambienttemperature of pharmaceutical preparations to the nasal passages ofhuman subjects, said preparations comprising at least 0.10% w/v and nomore than 2.5% w/v PVP-I and where at least 50% of the PVP-I is notassociated with liposomes or other particulate carriers.

Accordingly in one aspect, the present invention provides a method oftreating the common cold in a human subject caused or potentially causedby a virus, the method comprising applying to the nasal passages of thehuman subject at ambient temperature, an effective amount of apharmaceutical preparation comprising povidone-iodine (PVP-I) at aconcentration of between 0.10% and 2.5% w/v and in which at least 50% ofthe PVP-I is not associated with liposomes or other particulatecarriers.

In another aspect the present invention provides a method of reducingthe activity, viability or number of viruses within the nasal passagesof a human subject, wherein the viruses are causative or potentiallycausative agents of the common cold, the method comprising applying tothe nasal passages of the human subject at ambient temperature, aneffective amount of a pharmaceutical preparation comprisingpovidone-iodine (PVP-I) at a concentration of between 0.10% and 2.5% w/vand in which at least 50% of the PVP-I is not associated with liposomesor other particulate carriers.

In another aspect the present invention provides a method of reducingthe symptoms of the common cold in a human subject caused or potentiallycaused by a virus, the method comprising applying to the nasal passagesof the human subject at ambient temperature, an effective amount of apharmaceutical preparation comprising povidone-iodine (PVP-I) at aconcentration of between 0.10% and 2.5% w/v and in which at least 50% ofthe PVP-I is not associated with liposomes or other particulatecarriers.

In another aspect the present invention provides a method of reducingthe duration of the common cold in a human subject caused or potentiallycaused by a virus, the method comprising applying to the nasal passagesof the human subject at ambient temperature, an effective amount of apharmaceutical preparation comprising povidone-iodine (PVP-I) at aconcentration of between 0.10% and 2.5% w/v and in which at least 50% ofthe PVP-I is not associated with liposomes or other particulatecarriers.

In another aspect the present invention provides a method of reducingthe risk, incidence or severity of a secondary illness associated withthe common cold in a human subject caused or potentially caused by avirus, wherein the secondary illness is selected from the groupconsisting of bronchitis, otitis media and sinusitis, the methodcomprising applying to the nasal passages of the human subject atambient temperature, an effective amount of a pharmaceutical preparationcomprising povidone-iodine (PVP-I) at a concentration of between 0.10%and 2.5% w/v and in which at least 50% of the PVP-I is not associatedwith liposomes or other particulate carriers.

In another aspect the present invention provides a method of reducingthe risk, incidence or severity of lower respiratory illness associatedwith the common cold caused or potentially caused by a virus and inhuman subjects who suffer from COPD, asthma, emphysema or cysticfibrosis, or individuals with compromised immunity, the methodcomprising applying to the nasal passages of the human subject atambient temperature, an effective amount of a pharmaceutical preparationcomprising povidone-iodine (PVP-I) at a concentration of between 0.10%and 2.5% w/v and in which at least 50% of the PVP-I is not associatedwith liposomes or other particulate carriers.

In another aspect the present invention provides a method of preventingor reducing the risk of transmission of the common cold from a humansubject with symptoms of the common cold to uninfected human subjects,the method comprising applying to the nasal passages of the humansubject with cold symptoms, at ambient temperature, an effective amountof a pharmaceutical preparation comprising povidone-iodine (PVP-I) at aconcentration of between 0.10% and 2.5% w/v and in which at least 50% ofthe PVP-I is not associated with liposomes or other particulate carriersand wherein the causative or potentially causative agent of the commoncold is a virus.

In another aspect the present invention provides a method of avoidingthe common cold in a human subject who has been exposed to others withcommon cold symptoms, the method comprising applying to the nasalpassages of the human subject at ambient temperature, an effectiveamount of a pharmaceutical preparation comprising povidone-iodine(PVP-I) at a concentration of between 0.10% and 2.5% w/v and in which atleast 50% of the PVP-I is not associated with liposomes or otherparticulate carriers and wherein the causative or potentially causativeagent of the common cold is a virus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph derived from a mathematical model of an HRV infectionof the nasal passages, and shows the predicted viral load over timeduring a typical common cold for untreated subjects and those treatedwith intranasal PVP-I commencing at 24 hours after first symptoms andaccording to the preferred treatment method.

FIG. 2 is a graph showing the projected symptom severity scores from themathematical model as a function of time for untreated subjects andthose treated with intranasal PVP-I commencing at 24 hours after firstsymptoms and according to the preferred treatment method.

FIGS. 3 to 6 are graphs showing the actual results for each of 4subjects with colds who were treated with intranasal PVP-I according tothe preferred method. Each of the graphs shows the symptom severitymeasured as Total Symptom Scores (TSS) as reported at each scoring eventover 4 days for each of the 4 subjects with typical cold symptomscompared with typical mean daily TSS results for untreated patients asreported in published studies where a placebo control arm was used.

FIG. 7 is a graph showing the mean daily TSS results for the above 4subjects compared with typical mean daily TSS results for untreatedpatients as reported in published studies where a placebo control armwas used.

FIGS. 8 to 11 are graphs showing the TSS results for 4 colds experiencedby 2 subjects when subjects commenced treatment with PVP-I at the firstsigns of a cold, rather than 24 hours after first symptoms as in FIGS. 3to 7.

FIG. 12 is a graph showing the mean daily TSS results for the 4 coldsfrom FIGS. 8 to 11 compared with typical mean daily TSS results foruntreated patients as reported in published studies where a placebocontrol arm was used.

FIG. 13 is a graph showing the mean daily TSS results when treatmentcommenced at first symptoms compared with treatment commencing at 24hours after first symptoms and further compared with typical mean dailyTSS results over a similar time period for untreated patients asreported in published studies where a placebo control arm was used.

DEFINITIONS

In this patent specification, adjectives such as first and second, leftand right, front and back, top and bottom, etc., are used solely todefine one element or method step from another element or method stepwithout necessarily requiring a specific relative position or sequencethat is described by the adjectives. The terms “comprises,”“comprising,” “includes,” “including,” or similar terms are intended tomean a non-exclusive inclusion, such that a method, system or apparatusthat comprises a list of elements does not include those elementssolely, but may well include other elements not listed.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as would be commonly understood by those ofordinary skill in the art(s) to which this invention belongs.

As used herein, the terms “common cold” or “cold(s)” refers to aninfection of the nasal passages as defined herein that causes local andsystemic symptoms, the constellation of which is generally defined asthe common cold. This definition excludes secondary illness such asbronchitis, sinusitis and otitis media.

As used herein, “free iodine” refers to that elemental or diatomiciodine which is in solution and not actually bound to the polymer, inthe case of povidone-iodine, although it may initially have been sobound. The free iodine concentration represents the instantaneousmicrobicidal potency of the iodophor solution and is measured accordingto methods taught in U.S. Pat. No. 3,028,300 to Cantor, incorporatedherein by this reference.

As used herein, “available iodine” refers to that iodine of the iodophorwhich is ultimately available to be released from the polymer as freeiodine. It therefore includes free iodine in solution, diatomic iodineavailable from tri-iodide ions as well as diatomic iodine held within areservoir formed by the polymer structure. The available iodine does notinclude iodide ions. Available iodine is measured by thiosulfatetitration in accordance with United States and British Pharmacopeiamonographs.

As used herein, “total iodine” refers to all forms of iodine includingfree iodine, available iodine, iodide, iodate and other charged speciesof iodine in solution.

As used herein, “effective amount” refers to the dosage volume andfrequency of the administration of a pharmaceutical preparationcontaining PVP-I according to the inventive method, which is sufficientto be effective in the application. The effective amount will vary in amanner which would be understood by a person of skill in the art withpatient age, sex, weight, nasal passage volume etc. An appropriatedosage and dosage frequency can be ascertained through routine trial.

As used herein, “PVP-I NS” refers to a pharmaceutical preparationcontaining PVP-I for intranasal use as broadly defined by the presentinvention, or when used in relation to the specific examples cited,refers to a 0.25% PVP-I nasal spray prepared as described in theexamples.

As used herein, “ambient temperature” refers to the temperature in theenvironment at which the method of the current invention is conducted.Typically ambient temperature will be about 10° C. to about 30° C.Importantly the term “ambient temperature” means that neither thepharmaceutical preparation nor the nasal passages of the subject to betreated are exposed to external heating in carrying out the method ofthe present invention.

“Viral shedding” refers to the amount or concentration of virus presentin nasal washings or other nasal sampling technique. As used herein, theterm is generally equivalent to the term “viral load” and “ExtracellularViral Load” or “EVL”, each of which terms refers to the concentration oramount of virus in the nasal passages during a cold.

As used herein, the term “liposome” has the normal meaning in the art,while “particulate carriers” means liposomes, microspheres,nanoparticles, Large Porous Particles (LPP) or laser-pulse polymercoated molecule preparations as generally defined, used and referencedin WO 99/60998 by Fleischer et al. As used herein, the term “liposomalPVP-I” or “liposomal PVP-I preparations” refers to all preparationscontaining PVP-I where the PVP-I is predominantly entrapped in liposomesor other particulate carriers. Conversely, the term “non-liposomalPVP-I” or “non-liposomal PVP-I preparations” refers to preparations ofPVP-I where the majority of the PVP-I is not entrapped, encapsulated orotherwise bound to liposomes or other particulate carriers.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises methods for the treatment and preventionof the common cold and sequelae, the methods in all cases employingapplication to the nasal passages of human subjects of non-liposomalPVP-I preparations at ambient temperature where the concentration ofPVP-I is between 0.10% and 2.5% w/v. The inventive methods producesubstantial positive outcomes in key clinical measures of the commoncold, including reducing the severity of symptoms and the duration of acold and thereby constitute methods for the effective treatment of thecommon cold.

The inventive methods further provide benefits in terms of reducedincidence, risk or severity of common secondary illnesses, such assinusitis, bronchitis and otitis media. The methods further providebenefits in terms of reduced incidence, risk or severity of serious LRIand disease exacerbations in at-risk patient populations. The methodsfurther provide benefits in terms of reduced viral shedding from thenasal passages and thereby reduced risk of transmission of the cold tofamily members and others. The methods further provide benefits in termsof avoiding acquiring the common cold when subjects are exposed to coldsfrom other people.

The present discovery that non-liposomal PVP-I preparations can beeffective in treating and preventing colds has been made in spite of allthe limitations known in the art and previously outlined herein, whichin the absence of the present disclosures would not lead one skilled inthe art to conclude that PVP-I preparations as disclosed might be safeand effective in such applications.

One inventive step leading to this discovery by the present inventorswas the creation by them of a mathematical model of the course of atypical cold caused by HRV. This model, referred to herein as the “HRVmodel” is further elaborated in Example 1. The HRV model integratesassumptions, data and relationships about and between numerous variablesaffecting the viral load and cold symptoms during a cold caused by HRVand thereby provides a prediction of viral load and symptoms of atypical HRV cold over the time course of an HRV cold. The HRV modelfurther integrates and incorporates the effect of PVP-I preparationsapplied to the nasal passages according to the inventive method andenables prediction of the effect of such application on viral load andsymptoms over the time course of a cold.

Using the HRV model, the present inventors have discovered that whilePVP-I may have relatively weak activity against HRV, and further thatany such effect may be significantly depreciated by inactivation andclearance, when used according to the inventive method, PVP-I can beeffective in significantly reducing the HRV viral load in the nasalpassages. Further, this reduction surprisingly leads to a significantreduction of cold symptoms and cold duration. Given that HRV is the mostresistant known virus to the action of PVP-I, the predicted activityagainst HRV by the model would indicate that the inventive methods wouldbe at least as effective in treating colds caused by other moresensitive viruses.

Based on the data previously referenced by Wutzler et al (2002) andReimer et al (2002), under ideal in vitro conditions, one could expectthat non-liposomal PVP-I preparations at suitable concentrations for usein the nasal passages would produce approximately a 1.6 log reduction(97.5% reduction) in HRV viral load in two minutes, which is areasonable approximation of the time for exposure of the virus to PVP-Igiven clearance effects during a cold. Further, allowing fordepreciation of that performance due to inactivation by mucins andorganic material in the nose, including viruses and cells, a net percentreduction in viral load after each application can be estimated. Forexample, if the depreciative effect of inactivation is 50%, then theeffective reduction in HRV viral load with each PVP-I application dropsto 38.8%; if the depreciative effect is further increased to 80%, thenthe effective reduction in HRV viral load drops to 19.5%. However,according to the model and with a suitable frequency of application,even a viral load reduction of 19.5% after each application woulddegrade the viral load sufficiently over the course of the cold to causea significant reduction in viral shedding, the severity of cold symptomsand the duration of the cold. This surprising result is due to acombination of factors integrated into the model including the lowefficiency of cell infection and re-infection by HRV, the fact that acritical number of HRV virus particles is needed to initiate andperpetuate an infection, the relatively long infection cycle for HRV andthe frequency of repeated applications of the PVP-I preparation.

The model also surprisingly predicts that regardless of whether thePVP-I preparation according to the inventive method is first introducedat 24 hours, 48 hours or 72 hours after first symptoms, the methodproduces a subsequent substantial reduction in symptoms and coldduration. Thus the use of PVP-I as a treatment for the common cold wouldnot be encumbered by the short intervention window generally considereda barrier or limitation for any cold treatment.

The present inventors verified the outcomes predicted by the HRV modeland the effectiveness of inventive method in treating the common cold bypilot clinical test results as further described in Examples 2 and 4.Example 2 showed that in people who had confirmed colds for at least 24hours prior to treatment, a PVP-I preparation according to the inventivemethod is effective in treating HRV colds and colds caused by otherviruses, as measured by a reduction in total symptom scores (TSS) andcold duration or Time to Alleviation of Illness (TAI). Example 4 showedthat in people who had the first signs of a cold, a PVP-I preparationaccording to the inventive method is effective in reducing TSS by morethan 90% overall and in preventing cold symptoms reaching a level wherethey would otherwise impair the person's daily activities.

While viral load was not directly assessed in the studies, given thatthe primary mode of action of PVP-I is based on the destruction of virusby free iodine as predicted by the HRV model, it reasonably must beconcluded that the activity, viability and/or number of viruses in thenasal passages would be reduced and thereby viral shedding from the nosewould be reduced.

Further, by suppressing the viral load and shortening the period duringwhich virus is present in the nasal passages and reducing cold symptomsespecially mucous secretions, the inventive methods would reduce theincidence or severity of secondary illness, such as bronchitis, otitismedia and sinusitis. This is because the reduced viral load and mucoussecretions would reduce the risk of migration of significant amounts ofinfectious viruses to secondary locations such as the bronchi, middleear and sinuses, respectively. Examples 2, 3 and 4 provide furtherevidence of this effect.

Similarly, by suppressing the viral load, shortening the period duringwhich virus is present in the nasal passages and reducing mucoussecretions, the inventive methods would reduce the risk and/or severityof serious LRI and/or exacerbations of underlying respiratory diseasesin at-risk individuals.

Similarly, by suppressing the viral load, shortening the period duringwhich virus is present in the nasal passages and reducing mucoussecretions, the inventive methods would reduce the risk of transmissionof the virus from infected individuals to other people.

The inventive methods are also effective in preventing or avoiding coldsin people who have not yet acquired a cold but are exposed to otherswith cold symptoms. In relation to prevention of colds, some of theconsiderations pertinent to treatment do not apply. Notably, the purposeof the intervention with the PVP-I preparation is not principally toreduce the viral load and interrupt the infection cycle therebyshortening the duration of colds, nor principally to remove immunogenicstimulators and thereby reduce local and systemic symptoms of a cold.Rather, it is to destroy cold viruses in the nasal passages before theyhave the opportunity to infect nasal cells or to destroy cold virusesafter their release during early cycles of cell infection before coldsymptoms first appear or to destroy cold viruses at the first signs of acold and before cold symptoms have a chance to fully develop. Asdescribed in Example 3, PVP-I preparations according to the inventivemethod, and when used after an individual is exposed or may have beenexposed to a cold, reduced the incidence of significant colds byapproximately 88% over an 18 month period. Further as shown in Example4, PVP-I preparations according to the inventive method, and when usedafter an individual first detects cold symptoms, prevented colds fromflourishing and eliminated the impairment typically associated with coldsymptoms.

In addition to the predicted direct effects of the inventive PVP-Ipreparations in degrading the viral load during a cold, and withoutwishing to be bound by any specific theoretical explanations, thepresent inventors believe that the surprising, favourable outcomesobserved in treating and preventing the common cold may be due to thepropitious and unexpected interaction of several other mechanisms ofaction that in some cases augment or complement the direct effects ofPVP-I, or in other cases, and despite their apparent limiting effecttheoretically, may operate surprisingly favourably in practice tocontribute to effectiveness of PVP-I in treating colds. The combinationand interaction of these other mechanisms as an explanation for theeffectiveness of PVP-I in any illness has not previously been disclosed.

By way of example, and again without wishing to be bound by any specifictheoretical explanations, the observed utility of intranasal PVP-I intreating colds, may be due in part to the effects of PVP-I on viralreceptor proteins on the surface of nasal cells and those proteins onthe surface of viruses that are essential for viral attachment and entryinto cells. As disclosed recently by Sriwilaijaroen et al (“Mechanismsof the action of povidone-iodine against human and avian influenza Aviruses: its effects on hemagglutination and sialidase activities.”Virology Journal 6.1 (2009): 124), PVP-I can block the attachment ofinfluenza virus to human cells by altering the binding proteins on thevirus and/or on the receptor proteins on the cell surface. Whileinfluenza virus is the known cause of only a small percentage of colds,it is likely that similar effects would occur with respect to HRV andother cold viruses. This effect could further explain and contribute tothe observed utility of PVP-I in treating colds and may also contributeto its effectiveness in preventing colds.

By way of further example and again without wishing to be bound by anyspecific theoretical explanations, the observed utility of PVP-I intreating colds, may be due in part to the fact that free iodineinteracts with many proteins and likely would damage and/or inactivateimmune signalling proteins in the nasal mucous. Konig et al (“Effects ofBetaisodona® on parameters of host defense.” Dermatology 195.Suppl. 2(1997): 42-48) demonstrated that PVP-I inactivated the cytokine TNF-αafter its release from immune cells. U.S. Pat. No. 8,303,994 to Kessleret al discloses that free iodine interfered with the binding betweenStaph aureus enterotoxin and T-cells causing the T-cells to stopreleasing cytokines. This possible effect could further explain andcontribute to the observed utility of PVP-I in treating colds.

By way of further example and again without wishing to be bound by anyspecific theoretical explanations, the observed utility of PVP-I intreating colds may be because of the toxicity of PVP-I against monocytesand granulocytes, and that this feature, rather than a limitation, maysurprisingly contribute favourably to the efficacious outcomes observedin treating colds with PVP-I according to the inventive method. This isbecause, by eliminating these cells, PVP-I stops the propagation andamplification of systemic symptoms that otherwise would be caused by therelease of cytokines from these cells. By way of further explanation,because the direct impact of PVP-I on viral load as predicted by the HRVmodel would be so profound over the course of a cold, the normal role ofthe immune cells in eliminating the viruses becomes largely redundant inthe treatment of the condition and their elimination by the toxiceffects of PVP-I, when imposed in the HRV model, has negligible impacton the course of the infection or symptoms when using PVP-I according tothe inventive method.

There are several aspects of the invention now outlined that representimportant components of the inventive methods. One important aspect ofthe present invention is that the PVP-I preparation according to theinventive method is a non-liposomal PVP-I preparation as defined herein.This is contrary to current thought in the art that espouses the use ofliposomal PVP-I preparations for intranasal uses such as eradication ofMRSA colonies, because of their reduced toxicity, prolonged action andimproved tolerability, as further described in Wutzler et al (2002) andGluck et al (2007), both previously referenced herein. Liposomal PVP-Ipreparations are more fully described by Reimer et al (“Povidone-iodineliposomes an overview.” Dermatology 195.Suppl. 2 (1997): 93-99) andtypically entail the encapsulation of the majority of the PVP-I in apreparation in a multilaminar or unilaminar vesicle. This and otherreferences cited herein suggest that these properties may be useful inpreventing or treating infections of the eye, preventing infections inwounds and eradicating antibiotic-resistant bacteria from nasalpassages, in all cases where prolonged residence and antimicrobialeffect in conjunction with low toxicity and high tolerability may beimportant.

In liposomal PVP-I preparations, the vast majority of the PVP-I isencapsulated in a liposome and a small proportion of the PVP-I and/orfree iodine is outside the liposome in aqueous solution and in a form ofequilibrium with the PVP-I and/or free iodine inside the liposome.However, only the free iodine outside the liposome is available forinteraction with microorganisms. This two-phase system(liposomal-aqueous) ensures a relatively low level of active agentoutside the liposome, which is consistent with its reduced toxicity. PVPis inert and known to have no appreciable toxicity, so the only toxicityin PVP-I preparations, whether liposomal or non-liposomal, arises fromfree iodine. Therefore, it would be obvious to one skilled in the artthat the reduced toxicity of liposomal PVP-I preparations compared withnon-liposomal PVP-I preparations must be largely due to very low freeiodine levels outside the liposome. This is further evidenced by thereduced antimicrobial properties of liposomal PVP-I preparationscompared with aqueous PVP-I preparations, given that only free iodinehas any antimicrobial properties.

It is evident that the liposomal two-phase system retards the release ofPVP-I and/or free iodine, thereby providing for prolonged release overtime and longer duration of action in the absence of other factors. Thesystem also necessarily reduces the rate and/or quantum of replenishmentof PVP-I and/or free iodine into the aqueous phase in response todepletion of free iodine by antimicrobial action and inactivation, aswould occur during a cold. Accordingly, liposomal PVP-I preparations aregenerally not suited to the treatment of colds due to the lowinstantaneous levels of free iodine and the slow replenishment rate fromthe liposomal phase, which countervails the need for rapid action andhigh instantaneous potency during a cold, especially in the face of freeiodine inactivation and rapid clearance.

Further, liposomal PVP-I preparations are less effective against HRV.Wutzler et al (2002), previously referenced, compared liposomal andnon-liposomal PVP-I preparations for activity against HRV. After a 30second exposure, the aqueous PVP-I preparation produced a 1.1 logreduction (92% reduction) in virus compared with only a 0.2 logreduction (37% reduction) for the liposomal PVP-I preparation based onthe same concentration of PVP-I. After a 2-minute exposure, which islikely approaching the longest exposure time that could be achievedduring a cold, the reductions were 1.6 log (97.5%) and 0.6 log (75%)respectively. However, these tests were conducted under ideal in vitroconditions. During a cold, in the liposomal PVP-I preparation, the smallamount of active agent outside the liposome would be subject to rapidinactivation and dilution, and therefore would be expected to have anegligible direct effect on HRV viral load in vivo. Because of the slowreplenishment of active agent outside the liposomal phase, any prolongedeffect would be countervailed by rapid clearance and furtherinactivation. In summary, in the case of a cold, a more rapidly andaggressively acting agent is essential and the benefits of liposomalPVP-I preparations, i.e. reduced toxicity and longer duration of action,work against the desired outcomes in the treatment of the common cold.Therefore, the current invention strongly prefers that the PVP-Ipreparation is a non-liposomal preparation, where the majority of thePVP-I is not entrapped in liposomes, and all subsequent references toPVP-I preparations, formulations or solutions herein, unless otherwisespecified, refer to non-liposomal PVP-I preparations.

Another aspect of the present invention is that the PVP-I concentrationin the PVP-I preparation should be greater than 0.10% w/v to effect themost rapid and potent action during a cold, especially giveninactivation and clearance considerations. It is known in the art thatthe free iodine concentration in PVP-I solutions paradoxically increasesas the concentration of PVP-I is reduced from 10% to approximately 0.2%.The reason for this is that as a PVP-I solution is diluted, the freeiodine dissociates from the polymer-iodine complex and is released intosolution, thereby increasing the free iodine level and reducing theamount of available iodine that remains bound to the polymer. In thisregard, Atemnkeng et al (“Comparison of free and bound iodine and iodidespecies as a function of the dilution of three commercialpovidone-iodine formulations and their microbicidal activity.”International Journal of Pharmaceutics 317.2 (2006): 161-166) found thatat PVP-I concentrations below 0.10% the available iodine is greatlydepleted. As the PVP-I concentration is reduced below 0.05%, themajority of the available iodine is unbound from the complex and in theform of free iodine, such that the solution effectively becomes anaqueous iodine solution and any reservoir effect of PVP-I is eliminatedfor all practical purposes. In all cases, those in the art wouldconclude that for a PVP-I preparation to be effective and to effectivelyconstitute a PVP-I solution rather than a predominantly iodine solution,the majority of the free iodine needs to be bound to the polymer withonly a small minority of the free iodine in solution.

As further reported by Atemnkeng in the above cited reference, thehighest free iodine levels occurred when the PVP-I concentration wasbetween 0.1% and 0.5%. On this consideration, PVP-I concentrationsbetween above 0.1% and less than 1.0% are preferred, and concentrationsbetween 0.2% and 0.5% are most preferred.

The effect of intranasal agents on ciliated epithelium in the nose is animportant consideration around the use of a PVP-I preparation in thenose, because any ciliotoxicity can be detrimental to normal mucociliaryclearance function and any agent that causes ciliotoxicity may be deemedunsuitable for general or widespread use. Reimer et al (2002),previously referenced herein, note that PVP-I solutions containing 2.5%or higher concentrations of PVP-I were ciliotoxic causing a completeloss of ciliary function. However, a concentration of 1.25% or lower wasnot ciliotoxic. On this consideration, the composition for nasal useshould be a PVP-I concentration of less than 2.5% and preferably lessthan or equivalent to 1.25%.

With respect to the intranasal tolerability of PVP-I, as distinct fromciliotoxicity, the present inventors have discovered that when theconcentration of PVP-I in aqueous preparations is greater than 1.0%, thepreparation may be irritating to the nasal mucosa in some individualsand not suitable for repeated, frequent and general use, as would berequired in the effective treatment or prevention of the common cold. Onthis consideration, a preferred composition for nasal use is aconcentration of PVP-I at or below 1.0%.

A limitation previously identified that could affect the safety andutility of any PVP-I solution for intranasal use, especially in thetreatment and prevention of the common cold, is the likelihood of iodineabsorption and potential for excessive iodine uptake, with consequentelevated serum iodine levels and unwanted effects on thyroid function,especially in those people who have thyroid disease. In the UnitedStates, the National Institutes of Health guidelines state that the safeupper limit for iodine ingestion by adults is 1,100 micrograms of iodineper day. According to the methods of the present invention, a 0.6 mLdose delivered four times daily to an adult, would reach this upperlimit when the PVP-I concentration was 0.5%. However, the systemicbioavailability of the iodine available from a PVP-I preparation islikely to be significantly lower than the levels indicated by such acalculation. The iodine moiety principally absorbed and of concern withrespect serum iodine levels and thyroid function, is the iodide ion. Inthe treatment of the common cold where significant viral and otherprotein material is present, especially the glycoprotein mucin, asignificant proportion of any free iodine released from PVP-I wouldbecome irreversibly bound to proteins and not available for conversionto iodide ion or subsequent uptake into the bloodstream through nasalmucous membranes. Therefore, even at 1.0% PVP-I concentration, it isunlikely that iodide uptake would reach or exceed the safe daily limit.However, in a highly preferred embodiment, the PVP-I concentration forintranasal use would contain less than 0.5% PVP-I.

A final aspect of the present invention is that the application of thePVP-I preparation to the nasal passages occurs without the adjunctive orexternal use of heat to the nasal passages. Rhinothermy is a processrecently popularised for treating colds that involves the application ofheated and humidified air to the nasal passages. As reported by Aroll(“Non-antibiotic treatments for upper-respiratory tract infections(common cold).” Respiratory Medicine 99.12 (2005): 1477-1484),rhinothermy without adjunctive use of a microbicide can be effective intreating colds. PVP-I preparations are heat labile and the heating ofthe environment in which PVP-I preparations are applied may lead toinstability of the preparation, especially causing unpredictable orelevated instantaneous free iodine levels and otherwise increase therisk of allergic, toxic or other local reactions on the nasal mucosa. Itcould also lead to enhanced iodine absorption, systemic toxicity andother unwanted effects. Therefore, an aspect of the present invention isthat the application takes place at ambient temperatures, especiallybelow 100° F., and without the use of external or adjunctive heating.

In summary, the present invention recognises and concludes that thesurprising positive treatment effects of PVP-I on the common cold asoutlined in Examples 1, 2, 3 and 4, may be the outcome of thecombination of several propitious actions including (a) the degradationof the activity, viability and/or number of viruses in the nasalpassages to interrupt the infection cycle and remove the immunogenicstimulators of the immune response as described Example 1, (b) thedirect disruption of the cellular immune response by the reduction ofthe viability of immune cells, and (c) inhibition of viral attachment totarget cells through denaturation or alteration of binding proteins oncells or viruses. There may be other effects, not described herein, thatfurther contribute to the observed effectiveness of PVP-I in treatingcolds.

Further, the present invention recognises that liposomal PVP-Ipreparations are unsuitable for use in the treatment of the common coldand strongly prefers non-liposomal PVP-I preparations. Further, thepresent invention recognises that the concentration of the PVP-I must begreater than 0.10% for the solution to effectively constitute a PVP-Isolution and to have sufficient antimicrobial capacity to be effectivein the treatment or prevention of the common cold. Further, the presentinvention recognises that due to safety, tolerability and ciliotoxicityconsiderations, the concentration of PVP-I in the preparation should beless than 2.5%, preferably less than or equal to 1.0% and morepreferably less than or equal to 0.5%.

Prior art discloses methods for using certain iodine or PVP-I basedpreparations for treating or preventing certain respiratory conditions,but only some address the use of PVP-I in the treatment or prevention ofthe common cold, and none of these discloses or anticipates theinventive methods disclosed herein.

U.S. Pat. No. 6,171,611 to Picciano, incorporated herein by thisreference, discloses an iodine nasal solution and method for preventingand/or treating sinusitis and related conditions by applying thesolution to the nostrils of affected patients. This reference does notdisclose the use of PVP-I, nor does it disclose the treatment orprevention of the common cold.

United States Patent Application Publication No. 2006/0280809 byLeshchiner et al., incorporated herein by this reference discloses thatPVP-I can be used to treat ear and nasal infections, and to that endclaims pharmaceutical compositions containing between 5% and 50% PVP-Icombined with certain excipients, especially oils, and certain vehicles,especially glycosaminoglycans. There is no disclosure of the treatmentor prevention of the common cold with PVP-I and the proposed PVP-Iconcentrations are outside the range of the present invention and knownto be toxic in the nasal passages.

United States Patent Application Publication No. 2010/0203166 byRezakhany, incorporated herein by this reference, discloses methods forinhibiting respiratory infections by agitating or gargling an oral rinseor mouthwash in the throat and allowing vapours to penetrate the nasalpassages, wherein iodine may be an ingredient in the oral rinsesolution. It does not refer to any composition utilising PVP-I nor anyintranasal method for treating or preventing the common cold.

U.S. Pat. No. 5,038,769 to Krauser, incorporated herein by thisreference, discloses a method and apparatus for treating the common coldthat involves the application of air heated to above 100° F. to thenasal passages followed by a microbicidal agent in a nasal spray, wherethe microbicide could comprise a 0.5% PVP-I solution. The methoddisclosed in all cases requires the prerequisite and concomitantapplication of heated air to the nasal passages. The use of a PVP-Ipreparation at ambient temperature without the application of heated airis not disclosed.

U.S. Pat. No. 7,297,344 by Fleischer et al, incorporated herein by thisreference, discloses liposomal PVP-I preparations for use in the nasalpassages and identifies one highly preferred use as “the local treatmentof infections of the nose, mouth and throat” with specific examplesincluding herpes simplex virus infections and opportunistic infectionsassociated with immune deficiency states such as HIV and after organtransplantation, acute and chronic laryngopharyngitis, angina, andtissue repair applications especially in functional and cosmetic tissueremodelling. Methods for treating or preventing the common cold are notdisclosed, nor is the use of PVP-I preparations other than liposomalPVP-I preparations.

U.S. Pat. No. 6,694,041 and associated application US 2003/0180380 A1 toHansen, incorporated herein by this reference, disclose a method fortreating or preventing the common cold by using a nasal spray comprisingan iodine solution in combination with certain salts. In all cases, thepatent specifies the use of iodine in combination with other halogensalts or zinc gluconate and based on context and exemplifications, the“iodine” refers to total iodine and especially iodide, rather than freeiodine. While PVP-I is disclosed as a possible source of some of theiodine, the exemplified preparations contain less than 0.05% PVP-I andtherefore constitute iodine solutions rather than solutions of PVP-I,and would be ineffective in treating or preventing the common cold andare outside the concentration range disclosed in the current invention.This patent provides only a suggestion of the use of PVP-I for thetreatment of the common cold but especially given the exemplificationsit would not lead one skilled in the art to the currently claimedinvention.

In summary, the present invention describes methods for the treatmentand prevention of the common cold, which are not disclosed oranticipated by the prior art.

Accordingly in a first aspect the present invention provides a method oftreating the common cold in a human subject, the method comprisingapplying to the nasal passages of the human subject at ambienttemperature, an effective amount of a pharmaceutical preparationcomprising povidone-iodine (PVP-I) at a concentration of greater than0.10% w/v and less than about 2.5% w/v and in which at least 50% of thePVP-I is not associated with liposomes or other particulate carriers andwherein the causative or potentially causative agent of the common coldis a virus.

In a second aspect the present invention provides a method of reducingthe activity, viability or number of viruses within the nasal passagesof a human subject, wherein the viruses are causative or potentiallycausative agents of the common cold, the method comprising applying tothe nasal passages of the human subject at ambient temperature, aneffective amount of a pharmaceutical preparation comprisingpovidone-iodine (PVP-I) at a concentration of greater than 0.10% w/v andless than about 2.5% w/v and in which at least 50% of the PVP-I is notassociated with liposomes or other particulate carriers.

In a third aspect the present invention provides a method of reducingthe symptoms of the common cold in a human subject, the methodcomprising applying to the nasal passages of the human subject atambient temperature, an effective amount of a pharmaceutical preparationcomprising povidone-iodine (PVP-I) at a concentration of greater than0.10% w/v and less than about 2.5% w/v and in which at least 50% of thePVP-I is not associated with liposomes or other particulate carriers andwherein the causative or potentially causative agent of the common coldis a virus.

In a fourth aspect the present invention provides a method of reducingthe duration of the common cold in a human subject, the methodcomprising applying to the nasal passages of the human subject atambient temperature, an effective amount of a pharmaceutical preparationcomprising povidone-iodine (PVP-I) at a concentration of greater than0.10% w/v and less than about 2.5% w/v and in which at least 50% of thePVP-I is not associated with liposomes or other particulate carriers andwherein the causative or potentially causative agent of the common coldis a virus.

In a fifth aspect the present invention provides a method of reducingthe risk, incidence or severity of a secondary illness associated withthe common cold in a human subject, wherein the secondary illness isselected from the group consisting of bronchitis, otitis media andsinusitis, the method comprising applying to the nasal passages of thehuman subject at ambient temperature, an effective amount of apharmaceutical preparation comprising povidone-iodine (PVP-I) at aconcentration of greater than 0.10% w/v and less than about 2.5% w/v andin which at least 50% of the PVP-I is not associated with liposomes orother particulate carriers and wherein the causative or potentiallycausative agent of the common cold is a virus. This aspect is premisedon the discovery that the method will reduce the volume of mucoussecreted, reduce the activity, viability or number of cold virusescontained in secreted mucous, and reduce the period during whichmicrobe-laden mucous is present, which one skilled in the art wouldconclude will contribute to a reduced risk of viruses migrating tosecondary sites in the respiratory tract to establish or contribute tosecondary illnesses.

In a sixth aspect the present invention provides a method of reducingthe risk, incidence or severity of lower respiratory illness associatedwith colds in human subjects who suffer from COPD, asthma, emphysema orcystic fibrosis, or individuals with compromised immunity, the methodcomprising applying to the nasal passages of the human subject atambient temperature, an effective amount of a pharmaceutical preparationcomprising povidone-iodine (PVP-I) at a concentration of greater than0.10% w/v and less than about 2.5% w/v and in which at least 50% of thePVP-I is not associated with liposomes or other particulate carriers andwherein the causative or potentially causative agent of the common coldis a virus. This aspect is premised on the discovery that the methodwill reduce the severity and duration of the initial cold infection,which in itself would contribute to a reduced risk of exacerbation ofunderlying respiratory illnesses. In addition, and as with the fifthaspect, by reducing the volume of mucous secreted, the activity,viability or number of microorganisms in secreted mucous, and the periodduring which microbe-laden mucous is present, the method will contributeto a reduced risk of viruses migrating to the lower respiratory tract toestablish a lower respiratory infection.

In a seventh aspect the present invention provides a method ofpreventing or reducing the risk of transmission of the common cold froma human subject with symptoms of the common cold to uninfected humansubjects, the method comprising applying to the nasal passages of thehuman subject with cold symptoms, at ambient temperature, an effectiveamount of a pharmaceutical preparation comprising povidone-iodine(PVP-I) at a concentration of greater than 0.10% w/v and less than about2.5% w/v and in which at least 50% of the PVP-I is not associated withliposomes or other particulate carriers and wherein the causative orpotentially causative agent of the common cold is a virus. This aspectis premised on the discovery that the method will reduce viral sheddingduring a cold by reducing the volume of mucous secreted, the activity,viability or number of cold viruses shed in mucous, and the contagiousperiod during which virus-laden mucous is present. It will also reducetransmission facilitating symptoms such as rhinorrhoea, sneezing,coughing and symptom-related activity such as nose blowing.

In an eighth aspect the present invention provides a method of avoidingor suppressing the common cold in a human subject who may not have coldsymptoms but has been exposed to others with cold symptoms, the methodcomprising applying to the nasal passages of the human subject atambient temperature, an effective amount of a pharmaceutical preparationcomprising povidone-iodine (PVP-I) at a concentration of greater than0.10% w/v and less than about 2.5% w/v and in which at least 50% of thePVP-I is not associated with liposomes or other particulate carriers andwherein the causative or potentially causative agent of the common coldis a virus. This aspect is premised on the discovery that the methodwill sufficiently inactivate any cold viruses entering the nasalpassages to prevent onset of the cold infection or that the method willeliminate or sufficiently inactivate cold viruses at an early stage inthe infection process and thereby abort or significantly diminish theinfection.

In a preferred embodiment, the concentration of PVP-I in the preparationis between about 0.1% and about 1.0% and more preferably between about0.2% and about 0.5% and most preferably between about 0.2% and 0.45%.

In a preferred embodiment at least 70%, preferably at least 80%, morepreferably at least 90% of the PVP-I is not associated with liposomes orother particulate carriers.

It is further preferred that the pharmaceutical preparation does notcontain liposomes.

In a preferred embodiment the causative agent of the cold is selectedfrom the group consisting of rhinoviruses, human coronaviruses,influenza viruses, human parainfluenza viruses, human respiratorysyncytial viruses, adenoviruses, enteroviruses other than rhinoviruses,metapneumoviruses and any combinations thereof, and in particularrhinoviruses.

In another preferred embodiment the pharmaceutical preparation isadministered into the nostrils of the human subject between 1 and 12times daily with between about 50 μL and about 1000 μL of thepharmaceutical preparation administered to each nostril for eachadministration of the preparation.

In another preferred embodiment the common cold symptoms affected aretypically selected from the group consisting of chills, headaches, achesand pain, tiredness, running nose, sneezing, cough, nasal congestion,sore throat and combinations thereof.

In another preferred embodiment, the pharmaceutical preparation mayfurther comprise an agent selected from the group consisting of adecongestant, antihistamine, analgesic, antipyretic, anti-inflammatory,steroid, cough suppressant or cough expectorant.

In another preferred embodiment the pharmaceutical preparation mayfurther comprise at least one pharmaceutically acceptable diluent,excipient or carrier. Typically, the pharmaceutically acceptable diluentor excipient is a flavour, sweetener, colouring agent, solvent, buffer,alcohol, polymer, surfactant or other diluent or excipient designed tooptimize the nasal delivery, intranasal distribution, stability,effectiveness, acceptability, tolerability or other useful features ofthe preparation. In the event that liposomes or liposome-forming agentsare included in the preparation, in all cases only a minority of thePVP-I in the preparation will be entrapped in the liposomes. One ofordinary skill in the art would be able to determine the appropriatetypes and quantities of carriers, diluents, or excipients to be used inthe pharmaceutical preparation for intranasal use as required by themethod.

In another preferred embodiment the pharmaceutical preparation is in adosage form selected from the group consisting of intranasal solutions,drops, sprays, gels, aerosols, or inhalants, but may include any otherdevice or formulation suitable for administering an effective amount ofthe PVP-I to the nasal passages.

In order that the nature of the present invention may be more clearlyunderstood preferred forms thereof will now be described with referenceto the following non-limiting examples.

Example 1

In order to verify and elucidate the benefits of the inventive method aswell as establish the optimum dosage frequency and duration of treatmentfor a PVP-I nasal preparation according to the inventive method, thepresent inventors created a mathematical model of a typical common coldinfection caused by HRV, using variables and assumptions derived frompublished information about HRV infections of the nasal passages andsymptomatology of the common cold. The model is referred in the presentinvention as the “HRV model” and predicts the extracellular viral load(EVL) over time from the moment of first infection through the followingnine days, which encompasses the typical total duration of a HRV cold.The HRV model incorporated assumptions about the replication rate andinfection cycle of HRV, based on published data, as well as assumptionsabout the number of viruses in the initial inoculum, cell re-infectionrates, the number of viruses released from each infected cell and thetiming and impact of the immune response on viral load. The list ofvariables incorporated into the model is shown in Table 1.

TABLE 1 Summary of Variables in HRV Model Variable Description Virionsin initial inoculum Number of viruses in the initial infection Virusinfection rate % of viruses in EVL that actually infect cells Virionsreleased per lysed cell Number of new viruses released from eachinfected cell when it ruptures Cell infection rate ceiling Max number ofcells that can be infected per hour Cell total infection ceiling Maxnumber of cells that can be infected in total Cell infection cycle(hours) Number of hours from cell infection to rupture Cell rupturetiming % of infected cells at any time that rupture each hour from 8-14hours after first infection Immune response delay Delay from infectionto start of immune response and attendant symptoms Immune system effecton EVL Rate at which the immune system reduces EVL

The model was calibrated by comparing the pattern of viral loadprojections from the model with the typical pattern of viral load forHRV infections based on data from four clinical studies where the viralload was measured over time after subjects were deliberately infectedwith HRV. These studies, incorporated herein by reference, are: SchiffG. et al, “Clinical Activity of Pleconaril in an Experimentally InducedCoxsackievirus A21 Respiratory Infection” Journal of InfectiousDiseases, 2000, 181:20-26; Hayden, F., et al. “Efficacy and safety oforal pleconaril for treatment of colds due to picornaviruses in adults:results of 2 double-blind, randomized, placebo-controlled trials”Clinical Infectious Diseases 36.12 (2003): 1523-1532; Gern J. et al,“Inhibition of Rhinovirus Replication In Vitro and In Vivo byAcid-Buffered Saline” Journal of Infectious Diseases, 2007,195:1137-1143; Turner R. et al, “Efficacy of Tremacamra, a SolubleIntercellular Adhesion Molecule 1, for Experimental RhinovirusInfection: A randomized Clinical Trial” JAMA, 1999, Vol 281, No 19, pp1797-1804.

In addition to predicting EVL over the normal course of a HRV infection,the model was designed to predict the severity of overall cold symptomsbased on the known relationship between EVL and symptoms from publisheddata. Symptom scores predicted by the model were calibrated by comparingthe pattern of symptom score projections from the model with the typicalpattern of symptom scores for HRV infections based on data from twoclinical studies where the symptoms were assessed in conjunction withHRV viral load (Schiff et al, 2000; Hayden et al, 2003, both referencedabove).

The expected effects of a PVP-I preparation as defined in the presentinvention were then imposed on the HRV model based on the knowncapability of PVP-I to reduce the viral load of HRV, the likely exposuretime of virus to PVP-I in the nasal passages during a cold, thedepreciative effect of inactivation on PVP-I performance, and applyingdifferent daily dosage frequencies, durations of treatment, and threedifferent delays before treatment commenced after first symptoms, namely24 hours, 48 hours and 72 hours. The model predicted that PVP-I wouldhave a rapid and significant impact on EVL, symptoms and cold durationregardless of whether the PVP-I was used 24, 48 or 72 hours after firstsymptoms. Clearly, the earlier the PVP-I intervention, the shorter thetotal duration of the cold, but unlike antiviral drugs which suffer froma limited window of time after first symptoms in which they must beused, the HRV model surprisingly predicted no similar constraint withPVP-I in that, even if first used 72 hours after first symptoms, PVP-Icaused a rapid decline in EVL and consequently in projected symptomseverity compared with untreated colds.

Model projections for EVL and symptoms based on a typical set of modelassumptions are shown in FIG. 1 and FIG. 2. Only the data for treatmentcommencing at 24 hours after first symptoms are shown in FIGS. 1 and 2,because a 24 hour delay is considered to reflect the expected normal andpractical delay in commencement of treatment after a subject firstnoticed cold symptoms. FIG. 1 shows the projected viral load in the noseas a function of time for subjects treated with PVP-I at 24 hours afterfirst symptoms and approximately 4 times daily thereafter, compared withtypical viral load (EVL) data for untreated subjects.

As shown in FIG. 1, the HRV model projected an initial decline in viralload followed by a “saw tooth” pattern reflecting the immediatedegradation of the EVL after each application followed by a series ofviral regrowth episodes as new viruses were released from infected cellsin between PVP-I applications. According to the HRV model, byapplication of PVP-I at 24 hours after first symptoms of a cold, thegrowth in the EVL could be interrupted, the EVL would remain suppressedand then would shrink to close to zero and nasal shedding effectivelywould cease within 3 days. This compares with up to 3 weeks of ongoingshedding for untreated HRV colds.

The projected symptom severity chart is shown in FIG. 2. The HRV modelpredicted that by preventing the initial peak in EVL and repeatedlydegrading the remaining EVL, PVP-I would rapidly reduce symptom severitycompared with untreated colds and if used at 24 hours after firstsymptoms, would shrink the total duration of colds from an average of 7days after commencement of treatment to as few as 2-3 days.

Alternative dosage schedules to the four times daily dosage wereassessed in the HRV model including longer treatment schedules and amore aggressive initial treatment regimen of initial hourly applicationsof the PVP-I nasal spray followed by 4 times daily application.Treatment with schedules longer than 5 days appeared to offer littlebenefit according to the HRV model. However, the more aggressive initialhourly treatment predicted a slightly more rapid outcome in terms ofresolution of symptoms.

Example 2

An experiment was undertaken by using a commercially-available PVP-Ipreparation containing 7.5% PVP-I. The nasal spray preparation for theexperiment was prepared by using 0.67 mL of the commercial preparationand mixing this with 20 mL of saline (approximately 1:30 dilution) toyield 0.25% PVP-I in a standard decongestant-type nasal spray bottlewith a capacity of approximately 25 mL that delivered approximately 100μL per pump action. In the context of this experiment, thispharmaceutical preparation may be referred to as “PVP-I NS”.

Four adults known to the inventors who were otherwise healthy and whohad recently caught colds agreed to participate. Three of the people hadcolds that occurred in the spring or the autumn, so it was highly likelythat they were caused by HRV. The fourth person had caught their coldduring winter and it presented with more severe initial symptoms than istypical of HRV colds and for both reasons therefore was likely caused bycoronavirus, influenza virus or RSV. Two of the suspected HRV coldsubjects, were instructed to spray three shots (approximately 300 μL)per nostril four times a day for four days. The third HRV person wasinstructed to use the same dosage of PVP-I NS hourly for the first fourhours followed by four times daily for a total of four days. The personwith the suspected non-HRV cold was similarly instructed to use thePVP-I NS hourly for the first four hours followed by four times dailyfor a total of four days.

Everyone started treatment approximately 24 hours after they firstnoticed cold symptoms. Participants completed a daily symptom diary andreported on five local symptoms (runny nose, cough, sneezing,congestion, sore throat) and three systemic cold symptoms (malaise,headache, and chills), in accordance with published and accepted methods(Jackson, G., et al. “Transmission of the common cold to volunteersunder controlled conditions: I. The common cold as a clinical entity.”AMA archives of internal medicine 101.2 (1958): 267-278). Symptoms werereported just prior to each dosage of PVP-I NS during the four days oftreatment and then on the morning of the fifth day.

Although the present study was not a placebo controlled clinical trial,there are published data available for placebo results from controlledand blinded common cold studies which provide a useful guide tocomparative performance. In this case, the placebo/untreated data werederived from Eccles et al (“Efficacy and safety of an antiviralIota-Carrageenan nasal spray: a randomized, double-blind,placebo-controlled exploratory study in volunteers with early symptomsof the common cold.” Respiratory Research 11 (2010): 108) withadjustments for differences in scoring methodologies.

Key measures of product performance used in the experiment were: (a)Total Symptom Scores (TSS) calculated as the mean daily sum of thesymptom scores for the eight local and systemic symptoms, and (b) Timeto Alleviation of Illness (TAI), determined by the time in days to reacha point where runny nose was absent and no other symptom scored higherthan “mild” in terms of severity. TSS has been used in some coldtreatment studies as the primary endpoint for establishment of treatmentefficacy, including a published study of carrageenan nasal spray as acold treatment as described by Eccles et al (2010) referenced above.Time to Alleviation of Illness was used as the primary endpoint in thephase III common cold study for the antiviral drug, pleconaril, asdescribed by Hayden et al (2003) previously referenced herein.

For subject 1, TSS increased initially on the first day of treatment butrapidly declined by the end of the first day and was significantlyreduced by the end of day 2 compared with day 1. By day 3, virtually allsymptoms were resolved. For subject 2, TSS dropped to around half theinitial level by the end of day 2 and virtually all symptoms wereresolved by day 4, although there was an ongoing non-impairing level ofsymptomatology for another two days. For subject 3, on the moreaggressive treatment schedule, the TSS dropped dramatically by the endof fourth hour of treatment and all significant symptoms had resolved bythe end of the second day. For subject 4, on the more aggressivetreatment schedule and with the suspected non-HRV cold, the coldsymptoms were initially not responsive to treatment, with TSS increasingsignificantly on the first day of treatment. However, by the end of thesecond day, TSS had fallen to 25% of the peak TSS level and by the endof the third day symptoms were almost fully resolved.

All participants found the treatment acceptable and none reported sideeffects, local irritation or other concerns. All indicated that theybelieved the PVP-I nasal spray was effective in rapidly resolving theircolds compared with their expectations about how their colds would havenormally progressed otherwise. Further, none of the participantssuffered from a secondary illness subsequent to their cold, includingsinusitis, otitis media or bronchitis.

Graphs showing the TSS results as reported by each subject during thecourse of the study are shown in FIGS. 3-6. These data show a consistentpattern for the three suspected HRV colds, although the reduction incold symptoms was significantly faster in the case of subject 3 wherethe more aggressive treatment schedule was adopted. The data for subject4 suggest a more resistant infection, which did not initially respond totreatment on day 1, but by the end of day 2 was non-impairing andthereafter quickly resolved. This is consistent with many non-HRV coldswhich can have more severe and intractable symptoms than HRV colds.

FIG. 7 and Table 2 show the mean daily TSS for each of the four subjectscompared with typical untreated mean daily TSS data compiled frompublished studies. These data show that PVP-I NS was effective inreducing cold symptoms compared with published data for untreated colds,with an average 57% reduction in mean daily TSS by day 2 of treatmentcompared with typical untreated symptom scores and virtually allsymptoms resolved by day 3 or 4, compared with up to eight days foruntreated colds.

TABLE 2 Mean Daily TSS Reduction with PVP-I NS Prior to Mean daily TSSby Day of Treatment PVP-I 1 2 3 4 5 Subject 1 10.4 8.4 4.4 2.6 0.0 0.0Subject 2 9.7 6.7 4.8 4.0 3.0 1.0 Subject 3 11.2 5.0 2.5 0.8 0.0 0.0Subject 4 6.0 10.0 8.8 3.0 1.3 0.5 Average 9.3 7.5 5.1 2.6 1.1 0.4Untreated (placebo) 9.3 10.8 11.8 12.1 10.6 8.7 Average % reduction in−30% −57% −78% −90% −96% symptoms versus untreated

The TSS data were compared with those reported for carrageenan nasalspray with standardising adjustments for the different scoring methods.In the carrageenan study reported by Eccles et al (2010) alreadyreferenced herein, the authors used the sum of the TSS for days 2, 3 and4 as their primary endpoint and against this, carrageenan nasal spraydelivered an overall reduction in symptom severity of approximately 25%versus placebo. Against the same endpoint, the reduction in symptomseverity with PVP-I NS in the present study was 74%.

While TSS is a useful measure for comparing treatments, it is notconsidered a valid clinical endpoint by some regulatory authorities,because it is an un-weighted composite of scores for eight differentsymptoms. A more valid measure is thought to be the Time to Alleviationof Illness (TAI), i.e. cold duration, which was the primary endpoint inthe pleconaril phase three study described by Hayden et al (2003),referenced previously herein. In the current study, the PVP-I NSresolved cold symptoms in 2.3 days on average compared with 6.3 days forpleconaril and 7.3 days for placebo, a difference of 5.0 days or a 68%reduction in cold duration for PVP-I NS compared with placebo.

Overall, the results obtained in the study indicate that intranasalPVP-I is effective in the treatment of the common cold. Further, thepattern of the treatment effects on the suspected HRV colds as shown inFIGS. 3-5 are generally consistent with the predictions of the HRV modeland support the proposition that PVP-I works in part by the degradationof the EVL to interrupt the infection cycle and remove the immunogenicstimulators of the immune response. In addition, the overall dramaticreduction in symptoms and abrupt shortening of cold duration, includingfor subject 4 after day 1, may be consistent with other PVP-I effectsincluding the disruption of the immune response by the reduction of theviability of immune cells and/or denaturation of signalling proteinssuch as cytokines and/or inhibition of viral attachment to target cellsthrough denaturation or alteration of binding or receptor proteins.

Example 3

One adult male person know to the inventors evaluated the performance ofusing PVP-I NS preventatively as a method of avoiding colds over aneighteen month period. The individual normally experienced up to sixsignificant colds each year, where a “significant” cold was consideredto be one where the symptoms led to impairment of daily activities andotherwise met the criteria for a common cold. This person used a PVP-INS for 18 months, including two winters, a period when overall henormally would have experienced a total of at least eight colds.

He used the same PVP-I NS preparation as employed in the treatmentexperiment in Example 2. He was instructed to use the product only whenhe encountered someone at home, work, traveling or elsewhere whoexhibited cold symptoms such as runny nose, sneezing or coughing. He wasinstructed to use the PVP-I NS twice daily for five days after eachencounter. The person was provided with a supply of the commercial 7.5%PVP-I preparation, saline solution and a supply of empty 25 mL nasalspray bottles. After each such encounter with a suspected cold sufferer,the person prepared approximately 20 mL of the PVP-I NS by diluting thePVP-I preparation 1:30 with saline and pouring the diluted solution intoa clean 25 mL nasal spray bottle. The freshly prepared solution was thenused twice daily for five days after the encounter. At the end of eachfive day period, the diluted PVP-I NS in the nasal spray device wasdiscarded and the device cleaned. During the period he was instructed tonote any cold symptoms he experienced.

At the end of the study period, the person reported that he hadexperienced only one significant cold during the 18 month period and hadexperienced no instances of secondary illnesses including bronchitis,sinusitis or otitis media, despite typically suffering from bronchitisor sinusitis as sequelae of colds in the past. In the one instance of asignificant cold, during the three days prior to first noticing coldsymptoms he had not observed or noted any encounter with another personwith cold symptoms and therefore had not been using the PVP-I NS.However, he reported that within 12 hours after noticing his coldsymptoms he commenced using the PVP-I NS four times daily and the coldresolved within a few days and caused only moderate impairment of dailyactivities for approximately one or two days only. These results wereconsistent with the results in Example 2. The user believed that the useof the PVP-I NS greatly reduced his risk of acquiring a cold during thetreatment period and to the extent that one cold did occur, the symptomswere greatly ameliorated and no secondary illness occurred.

Although a single person case, this study supports the proposition thattwice daily or more frequent use of PVP-I NS after encountering someonewith cold symptoms will help the person avoid catching a cold and reducethe incidence or severity of colds for the person. However, such aregimen is unlikely to avoid or prevent all colds in a user because oneis not always aware of the presence of cold viruses. Accordingly, onecould unknowingly touch a contaminated surface or breathe incontaminated aerosol without actually observing another person withobvious cold symptoms. It appears that this occurred in the singleinstance of a significant cold that was observed during the studyperiod. This example also supports the claim that use of the inventivemethod will reduce the risk, incidence or severity of secondaryillnesses associated with the common cold, such as bronchitis, otitismedia and sinusitis.

Example 4

An experiment was undertaken using the PVP-I NS preparation as describedin Example 2. Two adults known to the inventors and who were regularcold sufferers agreed to participate in the experiment designed to testthe effectiveness of PVP-I nasal spray in reducing or preventing coldsymptoms when applied at the first signs of a cold, in contrast to theexperiment reported in Example 2, where subjects were required to wait24 hours after first symptoms before commencing treatment. The subjectsare hereafter referred to as Subject 1 and Subject 2.

The study was conducted over one year. At any time during that period ifeither subject started to experience symptoms of a cold and wereconvinced the symptoms were those of a cold, they were instructed toprepare and start using PVP-I NS. After the first application, they wereinstructed to apply the product four times a day for a total of fivedays, or a total of approximately 20 applications. However, someflexibility was allowed in the actual frequency and number of theapplications in this case. Unlike Example 2, Subjects were asked to usethe product for five days rather than four, because they would bestarting effectively a day earlier in the overall symptom cycle. UnlikeExample 2, subjects were asked to continue reporting symptoms for twodays after completion of the five-day treatment or a total of sevendays. In all other material respects, the protocol and reporting werethe same as the experiment reported in Example 2.

The hypothesis tested in this experiment was that if the HRV modeldescribed in Example 1 is valid, then application of PVP-I NS at thefirst signs of a cold, which is typically approximately 24 hours afterviral infection starts in the nasal passages, should suppress the viralload before the infection has had a chance to flourish and in so doingwould (a) prevent the cold symptom complex from fully developing and (b)more significantly reduce overall cold symptoms, compared with startingPVP-I NS treatment 24 hours after first symptoms, as in Example 2, whenthe infection and cold symptoms are already flourishing and the symptomcomplex close to full development.

TSS was used as the primary endpoint. Unlike Example 2, TAI was notmeasurable, because due to the PVP-I NS treatment, in no case did theillness symptoms reach a point that could be used as a benchmark foreffective measurement of alleviation of illness. One benchmark that wasfound useful in this case for assessing severity of illness was whetheror not the illness reached an impairing level, which for the purposes ofthe experiment was defined as a TSS greater than 4.

Subject 1 contracted only one cold during the period while Subject 2experienced three. All four colds occurred during non-winter months (twoin autumn, two in spring) indicating the causative virus probably wasHRV in all cases. FIGS. 8-11 show the TSS data as reported by the twosubjects for the four colds. Each TSS data point was based on symptomdiary reports at each specific time, typically immediately before eachPVP-I NS application. In each case, the down arrows indicate theapproximate time of each PVP-I NS application.

Subject 1: For Subject 1/cold 1, hereafter referred to as S1/1, theperson used the nasal spray for a total of 21 applications over the fivedays. The PVP-I NS application almost immediately suppressed symptoms toa non-impairing level, i.e., a TSS score of 4 or less. However, symptomsrose to above the impairing level on day 5 before rapidly declining,with the cold completely resolved at the end of day 7 and withoutrecurrence of symptoms thereafter.

Subject 2: The second subject experienced three colds, referred tohereafter as S2/1, S2/2 and S2/3 with TSS results as shown in FIGS. 9,10 and 11 respectively. For S2/1, as shown in FIG. 9, the person used 20applications over the five days and applied the product four timesdaily. In this case, the symptoms, while perceptible throughout thefirst four days never rose to an impairing level and disappeared on day5. The subject stated they knew they had a cold during the five days,but symptoms remained at a low level and at no stage impaired theirdaily activities.

For S2/2, as shown in FIG. 10, the person also applied PVP-I NS 20 timesover 5 days although the frequency was less consistent than S1/1 orS2/1. Because their cold symptoms first appeared late afternoon on thefirst day, they applied the treatment twice on that day and six timesthe following day. By the morning of day 3 the subject was convincedthat they had no cold and consequently reduced applications to oncedaily. Surprisingly, on the morning of day 5, which was 58 hours aftersymptoms were last observed, mild local symptoms (sneezing, rhinorrhoea,congestion) returned, at which time the subject applied the PVP-I NStreatment hourly for four hours and the symptoms promptly disappearedagain. Symptoms then reappeared the next morning (congestion,rhinorrhoea), so the subject again used the PVP-I NS treatment hourlyfor three hours and symptoms finally disappeared without recurrence.Again, PVP-I NS suppressed symptoms to a non-impairing level throughoutthe course of the cold.

For S2/3 as shown in FIG. 11, the subject applied PVP-I NS 17 times over5 days. Symptoms disappeared after approximately 48 hours, but like S2/2re-emerged on several occasions over the next few days, each timeresolving, in this case after only a single application of PVP-I NS.

In this experiment, TAI (time to alleviation of illness) assessmentswere not possible, because the PVP-I NS intervention mostly preventedthe symptom complex from fully developing in the first instance. Onlyone case (S2/3) had symptomatology that met the criteria for “illness”as defined by the TAI endpoint (rhinorrhoea plus any other symptomgreater than mild), so measuring alleviation of illness was impossiblefor all practical purposes. In none of the four cases did subjectsexperience any secondary illness such as bronchitis, sinusitis or otitismedia, and none reported any sensitivity reactions, stinging or otherintolerance to the PVP-I NS preparation.

FIG. 12 and Table 3 show the mean daily TSS for each of the foursubjects compared with typical untreated mean daily TSS data compiledand extrapolated from published studies, notably Eccles et al (2010)already referenced herein. These data show that PVP-I NS was overalleffective in treating colds when used at the first signs of a cold, withan average 89% reduction in mean daily TSS by day 2 of treatmentcompared with typical untreated symptom scores and virtually allsymptoms resolved by day 3 or 4, compared with up to eight days foruntreated colds.

TABLE 3 Mean Daily TSS using PVP-I NS, 0-Hour Start of Treatment MeanTSS by Day of Symptoms 1 2 3 4 5 6 7 S1/1 1.4 1.5 2.1 2.9 5 2.4 0.8 S2/10.7 1.4 0.8 1.1 0.4 0 0 S2/2 2.9 0.3 0 0.6 0.6 0 0 S2/3 4.2 1.4 0.8 00.2 0.2 0 Average PVP-I NS 2.3 1.1 0.9 1.2 1.5 0.6 0.2 Untreated(placebo) 7.8 11 12 12 11 8.7 7.4 Average % reduction −71% −89% −92%−90% −86% −93% −97% in symptoms Vs untreated

FIG. 13 shows the comparative average mean daily TSS data for Examples 2and 4. On an area-under-the-curve (AUC) basis, the AUC difference overthe eight days after start of treatment was 77% when treatment started24 hours after first symptoms, compared 92% for the same eight-dayperiod when treatment started at the first onset of symptoms.

This experiment demonstrates several important features of theinvention. Firstly, it provides further evidence of the effectiveness ofthe inventive method, notably the aspect of avoiding or suppressing thecommon cold in people who have been exposed to cold viruses and not yetexperienced symptoms or as specifically assessed in this example, hadthe first signs of that a cold was developing. Secondly, the improvedeffectiveness of PVP-I NS when used at the first signs of a coldcompared with its use 24 hours after first symptoms is consistent withthe HRV Model in Example 1. Thirdly, the fact that symptoms oftenreturned after cessation or a reduction in frequency of treatment withPVP-I NS points to the importance of the frequency of application andother aspects of the inventive method. Fourthly, it demonstrated theeffectiveness of the method in preventing secondary illnesses such asbronchitis, sinusitis and otitis media.

ADVANTAGES OF THE INVENTION

Despite nearly half a century of research, there is no effectivetreatment or preventative available for the common cold. The common coldremains the most prevalent disease afflicting humankind and every yearleads to massive morbidity, personal suffering, hospitalisations, lossof productivity, medical system burden and costs, and contributes to theglobal crisis of increasing antibiotic resistance. The present inventiondiscloses novel methods that employ PVP-I for intranasal use, which aredemonstrably safe and effective in treating colds as measured byreduction of cold symptoms and shortening of the overall duration ofcold symptoms, as well as preventing colds.

The methods possess industrial applicability for the preparation of acommercial product for the treatment and prevention of the common cold.A commercial product based on the invention could be made readilyavailable at relatively low cost and for the first time would provide aproduct to effectively treat and prevent colds and significantly reducethe number of presentations of colds to doctors, thereby alleviating theburden on the doctors and freeing their time to address the growingneeds of ageing populations worldwide. Moreover, it would reduce thecosts to patients or governments associated with payment orreimbursement for such consultations. Moreover, it would greatly reducethe prescribing of antibiotics for colds and associated secondaryillnesses such as bronchitis, otitis media and sinusitis, thereby notonly further reducing patient and reimbursement costs, but importantly,making a significant contribution to reduced antibiotic resistance andallowing precious antibiotics to be reserved for serious bacterialdiseases. Moreover, it would reduce the risk, cost, morbidity, sufferingand hospitalization associated with serious lower respiratory tractillness and exacerbations that occur as sequelae of colds in susceptibleindividuals such as those with asthma, cystic fibrosis, emphysema andCOPD and those with compromised immunity. Finally, it would reduce theproductivity losses and overall morbidity and suffering associated withcolds in the general population and potentially for the first time bringto heel the most prevalent disease afflicting humankind.

The effectiveness of the methods disclosed for both treatment andprevention does not depend on the particular organism or genetic orantigenic makeup of the organism causing or potentially causing theinfections. The methods do not cause side effects, are well tolerated,and with respect to treatment of colds, can be used together withconventional therapeutic or palliative measures for colds, such asantihistamines, decongestants, analgesics, cough medicines, and othermedications to further enhance the effectiveness of the methods.

The inventions illustratively described herein can suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising,” “including,” “containing,” etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the future shown and described or anyportion thereof, and it is recognised that various modifications arepossible within the scope of the invention claimed. Thus, it should beunderstood that although the present invention has been specificallydisclosed by preferred embodiments and optional features, modificationand variation of the inventions herein disclosed can be resorted bythose skilled in the art, and that such modifications and variations areconsidered to be within the scope of the inventions disclosed herein.The inventions have been described broadly and generically herein. Eachof the narrower species and subgeneric groupings falling within thescope of the generic disclosure also form part of these inventions. Thisincludes the generic description of each invention with a proviso ornegative limitation removing any subject matter from the genus,regardless of whether or not the excised materials specifically residedtherein.

In addition, where features or aspects of an invention are described interms of the Markush group, those schooled in the art will recognisethat the invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. It is also to beunderstood that the above description is intended to be illustrative andnot restrictive. Many embodiments will be apparent to those of in theart upon reviewing the above description. The scope of the inventionshould therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled. The disclosures of all articles and references,including patent publications, are incorporated herein by reference.

1. A method of treating the common cold in a human subject in needthereof, the method comprising applying to the nasal passages of thehuman subject an effective amount of a pharmaceutical preparationcomprising povidone-iodine (PVP-I) at a concentration of greater than0.10% w/v and less than about 1.25% w/v and in which at least 50% of thePVP-I is not associated with liposomes or other particulate carriers andwherein the causative agent of the common cold is a virus selected fromthe group consisting of rhinoviruses, human coronaviruses, humanparainfluenza viruses, human respiratory syncytial viruses,adenoviruses, enteroviruses other than rhinoviruses, metapneumoviruses,and any combinations thereof, and wherein the application of thepreparation to the nasal passages is without exposure to externalheating.
 2. The method according to claim 1, wherein the PVP-Iconcentration in the pharmaceutical preparation applied to the nasalpassages is about 0.1% to about 1.0% w/v.
 3. The method according toclaim 2, wherein the PVP-I concentration in the pharmaceuticalpreparation applied to the nasal passages is about 0.2% to about 0.45%w/v.
 4. The method according to claim 1, wherein the pharmaceuticalpreparation does not contain liposomes.
 5. The method according to claim1, wherein the pharmaceutical preparation is administered into thenostrils of the human subject, between 1 and 12 times daily.
 6. Themethod according to claim 1, wherein the causative or potentiallycausative agent of the common cold is a rhinovirus.
 7. A method ofreducing the symptoms of the common cold in a human subject in needthereof, the method comprising applying to the nasal passages of thehuman subject an effective amount of a pharmaceutical preparationcomprising povidone-iodine (PVP-I) at a concentration of greater than0.10% w/v and less than about 2.5% w/v and in which at least 50% of thePVP-I is not associated with liposomes or other particulate carriers andwherein the causative agent of the common cold is a virus selected fromthe group consisting of rhinoviruses, human coronaviruses, humanparainfluenza viruses, human respiratory syncytial viruses,adenoviruses, enteroviruses other than rhinoviruses, metapneumoviruses,and any combinations thereof, and wherein the application of preparationto the nasal passages is without exposure to external heating.
 8. Themethod according to claim 7, wherein the PVP-I concentration in thepharmaceutical preparation applied to the nasal passages is about 0.1%to about 1.0% w/v.
 9. The method according to claim 8, wherein the PVP-Iconcentration in the pharmaceutical preparation applied to the nasalpassages is about 0.2% to about 0.45% w/v.
 10. The method according toclaim 7, wherein the pharmaceutical preparation does not containliposomes.
 11. The method according to claim 7, wherein thepharmaceutical preparation is administered into the nostrils of thehuman subject, between 1 and 12 times daily.
 12. The method according toclaim 7, wherein the causative or potentially causative agent of thecommon cold is a rhinovirus.
 13. The method according to claim 7 wherethe common cold symptom is selected from the group consisting of chills,headaches, aches and pain, tiredness, running nose, sneezing, cough,nasal congestion, sore throat and combinations thereof.
 14. A method ofreducing the activity, viability or number of viruses within the nasalpassages of a human subject in need thereof, wherein the viruses arecausative agents of the common cold, the method comprising applying tothe nasal passages of the human subject at ambient temperature ofbetween about 10° C. to about 30° C., an effective amount of apharmaceutical preparation comprising povidone-iodine (PVP-I) at aconcentration of greater than 0.10% w/v and less than about 2.5% w/v andin which at least 50% of the PVP-I is not associated with liposomes orother particulate carriers, wherein the virus selected from the groupconsisting of rhinoviruses, human coronaviruses, human parainfluenzaviruses, human respiratory syncytial viruses, adenoviruses,enteroviruses other than rhinoviruses, metapneumoviruses, and anycombinations thereof, and wherein the application of the preparation tothe nasal passages is without exposure to external heating.
 15. Themethod according to claim 14, wherein the PVP-I concentration in thepharmaceutical preparation applied to the nasal passages is about 0.1%to about 1.0% w/v.
 16. The method according to claim 15, wherein thePVP-I concentration in the pharmaceutical preparation applied to thenasal passages is about 0.2% to about 0.45% w/v.
 17. The methodaccording to claim 14, wherein the pharmaceutical preparation does notcontain liposomes.
 18. The method according to claim 14, wherein thepharmaceutical preparation is administered into the nostrils of thehuman subject, between 1 and 12 times daily.
 19. The method according toclaim 14, wherein the virus is a rhinovirus.